Nanog signaling in cancer promotes stem-like phenotype and immune evasion
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4077-4093. https://doi.org/10.1172/JCI64057.
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Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Abstract

Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell–like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.

Authors

Kyung Hee Noh, Bo Wook Kim, Kwon-Ho Song, Hanbyoul Cho, Young-Ho Lee, Jin Hee Kim, Joon-Yong Chung, Jae-Hoon Kim, Stephen M. Hewitt, Seung-Yong Seong, Chih-Ping Mao, T.-C. Wu, Tae Woo Kim

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Figure 7

Nanog expression in human cervical neoplasia specimens correlates with stage and outcome of disease.

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Nanog expression in human cervical neoplasia specimens correlates with s...
(A) Representative image of immunohistochemical staining of Nanog, Tcl1a, and pAkt expression in cervical tissue from patients with low-grade CIN, high-grade CIN, and cervical carcinoma. Boxed regions are displayed at high magnification in insets (scale bar: 200 μm). (B) Box plot depiction of IHC data. The IHC score is an index of Nanog, Tcl1a, or pAkt expression and was computed based on intensity and tissue area of positive staining. In box-and-whisker plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate the lowest and highest datum within 1.5 interquartile range of the lower and upper quartiles, respectively. Symbols indicate individual samples. Numbers associated with symbols indicate case numbers. (C) Kaplan-Meier plots for patients with cervical cancer stratified according to FIGO stage, lymph node metastasis, or Nanog, Tcl1a, or pAkt expression. For patients with high Nanog expression, mean disease-free and overall survival were 46.3 months and 53.6 months (n = 94), respectively. For patients with low Nanog expression, mean disease-free and overall survival were 54.6 months and 57.9 months (n = 76), respectively.